Acute Leukemias

General Characteristics of Acute Leukemias

• Each type of acute leukemia has unique characteristics.
• Multiple genetic lesions lead to the establishment of a leukemic process, including:
  • Detectable chromosomal rearrangements.
  • Numerical abnormalities.
  • Gene mutations.
• Acute leukemias are characterized by:
  • Presence of blasts and immature leukocytes in peripheral blood and bone marrow.

French-American-British (FAB) Classification

• Divides acute leukemias into two major divisions:
  • Acute Myeloid Leukemias (AMLs).
  • Acute Lymphoblastic Leukemias (ALLs).
• Subdivisions:
  • AMLs are grouped into eight subtypes (M0 through M7).
  • ALLs are grouped into three categories (L1 through L3).
• Classification based on morphological characteristics observed in Wright-stained cells in peripheral blood (PB) and bone marrow (BM).

FAB Subtypes of Acute Myeloid Leukemia (AML)

Cellular Morphology in FAB Classification of ALL

World Health Organization (WHO) Classification

• Rationale based on defining disease entities according to biological characteristics and genetic traits:
  • Increased emphasis on molecular analysis and flow cytometry.
• Classification of AML integrates:
  • Cellular morphology
  • Cytogenetics
  • Molecular genetics
  • Immunological markers
• Incorporates FAB classification into its categories.

WHO Classification of Acute Leukemias and Related Neoplasms

• Acute Myeloid Leukemia with Recurrent Genetic Abnormalities include:
  • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBEB-MYH11
  • AML with t(9;11)(p22;q23); MLLT3-MLL
  • More listed under provisional entities based on mutations and genetic rearrangements.

Prognostic Factors in Acute Leukemias

• Factors related to the patient include:
  • Age
  • Coexisting medical conditions
  • Overall health status
• Disease factors include:
  • Total leukocyte count
  • Previous cytotoxic therapy
  • Underlying genetic changes
• Approximately 70% of acute leukemia patients die from infection.
• Median survival for untreated patients is approximately 3 months.
• Remission rate:
  • 90% of children and 60-70% of adults achieve at least one remission.
• Best chance for longest remission and possible cure occurs at initial diagnosis.

Acute Myeloid Leukemia (AML) Characteristics

• Most common leukemia subtype.
• Definition: A genetically heterogeneous clonal disorder characterized by:
  • A maturation block.
  • Accumulation of acquired somatic genetic alterations impacting mechanisms of self-renewal, proliferation, and differentiation.
• Classification of AML subtypes is clinically relevant as specific abnormalities correlate with clinical behavior and prognosis.

Epidemiology of AML

• Approximately 13,000 new diagnoses of AML annually in the United States.
• Over 25% of adults with AML can expect to survive 3+ years and may attain a cure.
• Remission rates inversely related to age.
  • Patients over 55 have poorer prognosis.

Cytogenetic Analysis in AML

• Approximately 67% of AML patients show clonal chromosomal abnormalities; increases to 90% in secondary leukemia cases.
• Prominent chromosomal abnormalities include:
  • Gains or losses of entire chromosomes.
  • Deletions, translocations, and inversions (translocations are the most frequent).
• Malignant transformation is linked to activation of ordinary oncogenes via translocation-induced rearrangements.

Common Genetic Mutations in AML

Molecular Analysis in AML

• Next generation sequencing (NGS) yielding insights into mutations and clonal evolution.
• Clonal evolution demonstrates involvement of genes related to epigenetic regulation (e.g., DNMT3A, ASXL1, IDH2, TET2) in preleukemic hematopoietic stem cells.

Functional Categories of Genes Mutated in AML

Key Laboratory Findings in AML

• Anemia commonly observed, often due to bleeding and marrow replacement by leukemic blasts.
• Total leukocyte count can be highly variable:
  • Typically elevates, but some cases normal or reduced.
• Thrombocytopenia often present.
• Block in differentiation/maturation of immature hematopoietic progenitors is a hallmark feature.
• Myeloid-to-erythroid (M:E) ratio is elevated.

Laboratory Evaluation of AML

Prognosis of AML

• Cured in 35-40% of adults younger than 60 years; only 5-15% of those over 60 years.
• Older patients with intolerable chemotherapy experience a median survival of 5-10 months.
• Favorable prognosis associated with recurrent chromosome translocations (e.g., t(15;17), t(8;21)).
• Poor prognosis linked with complex karyotypes or chromosome loss.

MicroRNAs in AML

• MicroRNA expression correlates with cytogenetic, molecular, and morphological changes, influencing clinical outcomes.
• MicroRNAs are 19-25 nucleotide RNAs derived from longer precursors that target mRNA for degradation or translation inhibition.

Acute Myeloid Leukemia (FAB M0)

• M0 subtype: consisting of undifferentiated myeloid blasts.
• Exhibits reactivity with myeloperoxidase, hence classified as AML.

Acute Myeloid Leukemia (FAB M1)

• Known as acute myeloblastic leukemia without maturation.
• Most common in children younger than 18 months; median age in adults 46 years.
• Male:female ratio of 1:1; median survival 3.5 months.

Acute Myeloid Leukemia (FAB M2)

• Synonym: acute myeloblastic leukemia with maturation.
• Predominantly myeloblasts; typical middle-age occurrence.
• Median age: 48 years; male:female ratio 1.6:1; median survival 8.5 months.

Acute Promyelocytic Leukemia (FAB M3)

• Laboratory findings similar to FAB M2.
• Median age occurrence 38 years; median survival 16 months; male:female ratio 2:1.

Acute Myelomonocytic Leukemia (FAB M4)

• Rare in younger demographics; most frequent in those over 50.
• Male:female ratio, 1.4:1; average survival 8 months. Characterized by granulocyte/monocyte proliferation.

Acute Monocytic Leukemia (AMoL; FAB M5)

• Rare, constitutes less than 15% of leukemias with two forms (FAB M5A and M5B).
• M5A primarily affects younger individuals (median age 16 years), while M5B peaks at middle age (median 49 years).

Erythroleukemia (FAB M6)

• Synonym for M6A/B is acute erythroid leukemia.
• Median age 54, male:female ratio 1.4:1; average survival 11 months.
• Associated with Di Gugliamo’s syndrome, noted by mutated normoblasts.

Acute Megakaryoblastic Leukemia (FAB M7)

• Synonym: acute megakaryoblastic leukemia.
• Characterized by >50% of blasts originating from megakaryocyte lineage; constitutes 3-5% of AML cases.

Treatment Options for Acute Leukemias

• Improvements in diagnosis have enhanced leukemia patient outcomes.
• Advances include molecular insights leading to specific therapies:
  • Targeted therapies like imatinib (Gleevec).
  • Cytotoxic chemotherapy is intense - divided into phases:
  • Induction and Post-remission phases; major complications include infection and hemorrhage.

Induction Phase of Therapy

• Administration of multiple drugs to induce remission.
• Main therapy: cytarabine with an anthracycline.
• Intense treatments may include high doses of cytarabine alone or in combination with other agents.

Consolidation Therapy

• After remission, involves:
  • Conventional chemotherapy.
  • Hematopoietic stem cell transplant, preferably allogeneic despite higher mortality risks.

Relapse and Prognosis

• AML relapse is common and occurs predominantly within 3 years post-diagnosis.
• Higher likelihood of poor prognosis associated with aggressive recurrence.
• Favorable prognosis exists for those in remission over 1 year prior to relapse, with 20% survival possibility.

New Therapies for AML

Innovations in Drug Development include:

• Epigenetic modifiers.
• Tyrosine kinase inhibitors.
• Nuclear export inhibitors.
• Cytotoxic agents.

Acute Lymphoblastic Leukemia (ALL) Characteristics

• Most prevalent cancer in children, representing 23% of cancer diagnoses in those under 15.
• Shows bimodal age distribution: peaks at ages 3-5 and over 50.
• Slight prevalence in boys and in white children.

Pathogenesis of ALL

• Linked to genetic factors (e.g., Down’s syndrome, polymorphic gene variants) and environmental risks (radiation exposure, chemicals).

Classification of ALL

• Divided into FAB categories:
  • L1 (children), L2 (older children/adults), L3 (Burkitt’s lymphoma type).

Prognosis of Acute Lymphoblastic Leukemia

• About 85% of children survive 5 years; 78.1% survive 10 years.
• Treatment outcomes for adults lag behind those of children.

Treatment for ALL

• Differentiation between treatments for Philadelphia chromosome positive and negative cases:
  • Use of first- and second-generation ABL kinase inhibitors, improving adult treatment outcomes.

Life-Threatening Emergencies in Acute Leukaemias

• Common emergencies include:
  • Infection, bleeding, leukemic infiltration of organs, metabolic abnormalities, and hyperleukocytosis.

Future Trends in Treatment

• Investigating novel vaccines aimed at activating the immune system against AML/MDS cells featuring specialized peptides and adjuvants.